BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. INTERPRETATION: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. FUNDING: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.

Academic Center For Thyroid Disease Department of Internal Medicine Erasmus Medical Center Rotterdam Netherlands

Academic Center For Thyroid Disease Department of Internal Medicine Erasmus Medical Center Rotterdam Netherlands; Università Vita Salute San Raffaele Milan Italy

Centre for Endocrinology William Harvey Research institute Queen Mary University London London UK; Dept of Paediatric Endocrinology Barts Health NHS Trust London UK

Child Neurology Unit Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Departamento de Neurologia Pediatrica Clinica Las Condes Santiago Chile

Department of Cardiology and Intensive Care Medicine Erasmus Medical Centre Rotterdam Netherlands

Department of Child Neurology Center for Childhood White Matter Diseases Emma Children's Hospital Amsterdam University Medical Centers Vrije Universiteit Amsterdam and Amsterdam Neuroscience Amsterdam Netherlands

Department of Child Neurology Center for Childhood White Matter Diseases Emma Children's Hospital Amsterdam University Medical Centers Vrije Universiteit Amsterdam and Amsterdam Neuroscience Amsterdam Netherlands; Department of Pathology Amsterdam Neuroscience Amsterdam University Medical Centers Vrije Universiteit Amsterdam Amsterdam Netherlands

Department of Child Neurology University Medical Center Groningen University of Groningen Groningen Netherlands

Department of Diabetes and Endocrinology Women's and Children's Hospital North Adelaide SA Australia

Department of Endocrinology and Diabetes Queensland Children's Hospital South Brisbane QLD Australia; Department of Chemical Pathology Mater Pathology South Brisbane QLD Australia; Faculty of Medicine University of Queensland Brisbane QLD Australia

Department of Endocrinology St John's Medical College Hospital Bengaluru Karnataka India

Department of General Pediatrics Neonatology and Pediatric Cardiology University Children's Hospital Medical Faculty Duesseldorf Germany

Department of Human Genetics Donders Institute for Brain Cognition and Behaviour Radboud University Medical Center Nijmegen Netherlands

Department of Neuropediatrics University Children's Hospital Zurich Zürich Switzerland

Department of Paediatric Cardiology Addenbrooke's Hospital Cambridge University Hospitals NHS Foundation Trust Cambridge UK

Department of Paediatric Endocrinology and Diabetology Charité Universitätsmedizin Berlin Berlin Germany

Department of Paediatric Endocrinology and Genetics Children's Hospital Toulouse University Hospital Toulouse France

Department of Paediatric Neurology Addenbrooke's Hospital Cambridge University Hospitals NHS Foundation Trust Cambridge UK

Department of Paediatric Neurology Erasmus Medical Centre Rotterdam Netherlands

Department of Paediatrics 2nd Faculty of Medicine Charles University University Hospital Motol Prague Czech Republic

Department of Paediatrics AOU Città della Salute e della Scienza di Torino University of Torino Torino Italy

Department of Paediatrics Christian Medical College Vellore India

Department of Paediatrics Semmelweis University Budapest Hungary

Department of Pediatric Endocrinology and Diabetology University Hospital Angers France

Department of Pediatrics and Adolescent Medicine Faculty of Medicine University of Freiburg Freiburg im Breisgau Germany; KUNO Children's University Hospital Campus St Hedwig University of Regensburg Regensburg Germany

Department of Translational Medicine Federico 2 University Naples Italy; Telethon Institute of Genetics and Medicine Pozzuoli Naples Italy

Division of Endocrinology and Diabetes Children's Hospital of Philadelphia Perelman School of Medicine University of Pennsylvania PA USA

Division of Endocrinology Bambino Gesu' Children's Research Hospital IRCCS Rome Italy

Division of Neuropediatrics and Muscular Disorders Department of Pediatrics and Adolescent Medicine University Hospital Freiburg Freiburg Germany

Division of Paediatric Radiology Erasmus Medical Centre Rotterdam Netherlands

Division of Pediatric Endocrinology and Diabetology and Children's Research Center University Children's Hospital Zurich Switzerland

Division of Pediatric Endocrinology Faculty of Medicine Dokuz Eylul University İzmir Turkey

Emma Children's Hospital Department of Paediatric Endocrinology Amsterdam UMC University of Amsterdam Amsterdam Netherlands

Faculdade de Medicina Centro Universitario Estácio de Ribeirão Preto Ribeirão Preto Brazil

Genomics Institute Mary Bridge Children's Hospital MultiCare Health System Tacoma WA USA

Institute of Maternal and Child Research University of Chile Santiago Chile; Department of Pediatrics Clinica Las Condes Santiago Chile

John Hunter Children's Hospital and University of Newcastle Newcastle NSW Australia

Lancashire Teaching Hospitals NHS Trust Lancashire UK

Marmara University School of Medicine Department of Pediatric Endocrinology Istanbul Turkey

Medanta Superspeciality Hospital Indore India

Medical Genetics Service Hospital de Clínicas de Porto Alegre Porto Alegre Brazil

Medical University of Gdańsk Department of Paediatrics Haematology and Oncology Department of General Nursery Gdańsk Poland

Paediatric Endocrinology Diabetology and Gynaecology Department Necker Children's University Hospital Imagine Institute Paris France

Paediatric Endocrinology Unit Kaplan Medical Center Rehovot Israel; Hebrew University of Jerusalem Jerusalem Israel

Paediatric Neurology Clinic Alexandru Obregia Hospital Bucharest Romania; Department of Neurosciences Paediatric Neurology Discipline 2 Carol Davila University of Medicine Bucharest Romania

Panorama Medical Centre Cape Town South Africa

Pediatric Endocrinology Group Santa Catarina Hospital São Paulo Brazil

Pediatric Neurology Section Hospital Francesc de Borja de Gandia Valencia Spain

Plymouth Hospitals NHS Trust Plymouth UK

Regional Genetics Program Children's Hospital of Eastern Ontario and Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa ON Canada

Royal Children's Hospital Parkville Melbourne VIC Australia

Sheffield Children's NHS Foundation Trust Sheffield Hallam University and University of Sheffield Sheffield UK

Sophia Children's Hospital Division of Paediatric Cardiology Erasmus Medical Centre Rotterdam Netherlands

Teaching Hospital of Universidade Federal de Pelotas Pelotas Brazil

Unit of Medical Genetics and Neurogenetics Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy

Unit of Neuromuscular and Neurodegenerative Disorders Bambino Gesu' Children's Research Hospital IRCCS Rome Italy

University of Debrecen Pediatric Institute Debrecen Hungary

University of Lille Lille France

University of Louisville Louisville KY USA

Wellcome Trust Medical Research Council Institute of Metabolic Science University of Cambridge Cambridge UK

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Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration